Clinical trials of oral type II collagen (CII) in patients with rheumatoid arthritis (RA) have yielded somewhat conflicting and controversial results. All studies, regardless of design to date have allowed RA patients to continued on a daily regimen including a oral non-steroidal anti-inflammatory drug (NSAID). Basic studies in murine models have clearly shown that NSAIDs markedly inhibit immune tolerance induction to certain orally administered antigens. Our preliminary studies in the DBA/1 mouse CII-induced arthritis (CIA) models show that oral tolerance to bovine VII is markedly impaired in mice concomitantly fed oral NSAID. To adequately evaluate the effect of oral CII tolerance induction on clinical and immune parameters in RA patients, we propose that patients will have to be withdrawn from daily NSAIDs, which our animal data suggest interfere with the ability of the gut associated lymphoid tissue (GALT) to mount a tolerogenic response to orally administered CII. We, therefore, hypothesize that daily oral CII will induce tolerance to CII in RA patients off NSAIDs and other disease modifying anti-rheumatic drugs (DMARDs). The four Specific Aims of this application will 1) determine by use of a "balanced incomplete block design" which, if any, of 3 different doses of bovine CII (20 microgram/day) are superior in efficacy to a standard NSAID in RA patient with early disease; 2) determine in RA patients with demonstratable immunity to CII whether clinical improvement as a result of oral CII therapy is accompanied by a reduction in CII immunity; 3) determine in RA patients exhibiting a clinical response to oral CII treatment whether the peripheral blood T cell cytokine response to CII is altered; and 4) determine whether specific HLA-DR or-DQ genotypes are associated with a clinical response to oral CII treatment or with the presence of immunity to CII at entry into the study. In summary, by withdrawing NSAIDs, which interfere with oral tolerance induction, from RA patients we believe this study will fully explore the therapeutic potential of oral CII tolerance induction in RA.